Carnitine palmitoyltransferase II deficiency
Nov. 24, 2024
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Homocystinuria due to cystathionine beta-synthase deficiency …
- Updated 05.03.2023
- Released 09.17.2004
- Expires For CME 05.03.2026
Homocystinuria due to cystathionine beta-synthase deficiency
Introduction
Overview
Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism are the most common features in homocystinuria due to cystathionine beta-synthase deficiency. There are multiple causes for homocystinuria. This overview will focus on homocystinuria due to cystathionine beta-synthase deficiency. Despite manifestation of symptoms in childhood some affected individuals were discovered in the second to fourth decade only when presenting with severe thromboembolic complication. In this article, the author reviews this disease and explains why homocystinuria, particularly the pyridoxine-responsive and most readily treatable form of the disease, is still underrecognized.
Key points
• Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism affecting large and small arteries and veins are the most common clinical features of homocystinuria. | |
• Homocystinuria is a rare inborn error of metabolism caused by mutations in the cystathionine beta-synthase gene. | |
• There are 2 major types of homocystinuria due to cystathionine beta-synthase deficiency based on their response to B6 (pyridoxine). | |
• Homocystinuria due to cystathionine beta-synthase deficiency is screened for in some newborn screening programs. | |
• Total homocysteine in plasma, often higher than 200 µmol/L (normal < 15 µmol/L), and increase of plasma methionine allows diagnosis of cystathionine beta-synthase deficiency. | |
• Early and lifelong consequent treatment with diet and vitamins leads to significantly better outcome in affected patients. |
Historical note and terminology
Homocystinuria caused by cystathionine beta-synthase deficiency is an inborn error of the transsulfuration pathway. The disorder is biochemically characterized by accumulation of homocysteine, methionine, and a variety of other metabolites of homocysteine in the body and, ultimately, excretion in the urine. The disease was discovered in 1962 by Carson, Neill, and colleagues when individuals with intellectual disability were screened for abnormal urinary amino acids (13; 20). Two years later, the enzymatic defect was identified by Mudd and colleagues (62). Since then, considerable experience has defined the clinical phenotype, the abnormal biochemistry, and the natural history of the disease (65). Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism affecting large and small arteries and veins are the most common clinical features (65).
In 1967, Barber and Spaeth reported that 3 cystathionine beta-synthase-deficient patients responded to high doses of pyridoxine (vitamin B6), with decrease of plasma methionine levels to normal and virtual elimination of homocysteine from plasma and urine (07). This observation has since been extended to many additional patients by many authors. It became obvious that there are 2 distinct populations of patients with homocystinuria, one of which responds to treatment with pyridoxine and one that does not (27; 61; 65; 32). The autosomal recessive inheritance of cystathionine beta-synthase deficiency was reported by Finkelstein and colleagues in 1964 (21). The gene has been cloned and mapped to chromosome 21 in the subtelomeric area q22.3 (66). The human cystathionine beta-synthase cDNA sequence was published in 1993 (43). Crystallization and preliminary crystallographic analysis of a protein construct that contains the full-length cystathionine beta-synthase from Homo sapiens and crystallization of the catalytic core of this enzyme from Saccharomyces cerevisiae has been achieved (69; 18), and the structure of the human enzyme has been published (19).
Homocystinuria presents with elevated urinary homocysteine and plasma homocysteine. There are multiple causes that include genetic forms of inborn errors of metabolism related to interference with conversion of homocysteine to methionine and abnormalities of cobalamin transport or metabolism. In addition to genetic etiologies, homocystinuria can also be caused by acquired forms of secondary to severe cobalamin (B12) deficiency. Therefore, adding the enzyme to the end of the term “homocystinuria” provides the most accurate nomenclature, eg, homocystinuria due to cystathionine beta-synthase deficiency.
Clinical manifestations
Presentation and course
Cystathionine beta-synthase deficiency represents a multisystem disorder with involvement of the eyes, integument, skeleton, vascular system, and nervous system. The most comprehensive overview of clinical manifestations in cystathionine beta-synthase deficiency was given by Mudd and colleagues in 1985 when they investigated the natural course of the disease in 629 patients by an international questionnaire survey (65).
Eyes. Ectopia lentis is a striking and readily recognizable manifestation of the disease. It may be the only manifestation, and by 38 years of age only 3% of patients have both lenses in place. Dislocation is usually present by 10 years of age. The dislocation is usually downward--the opposite of the situation in Marfan syndrome. Other ocular abnormalities include myopia, glaucoma, cataracts, retinal detachment, and, rarely, optic atrophy.
Skin and hair. The skin and hair may show a decrease in pigment. A pronounced malar flush was first recognized in Ireland (12). The skin may otherwise have blotchy erythema and pallor. Livido reticularis is particularly common in the distal extremities, which may be cold and show other evidence of vascular instability (26).
Skeletal system. Generalized osteoporosis is the most common skeletal finding, and 50% of patients have osteoporotic changes in the radiograph of the spine at the age of 16 years (65). Low bone mineral density was found in 38% of patients when investigated by DEXA scan (84). There are a large number of other skeletal abnormalities, including genu valgum, everted feet, pectus excavatum or carinatum, scoliosis, biconcave (“codfish”) vertebrae, large metaphyses, and epiphyses. Notable among these is dolichostenomelia (thinning and lengthening of the long bones), which produces tall and thin individuals who are often considered to have a marfanoid appearance, but true arachnodactyly is rare (74; 10).
Vascular system. Thromboembolism is the major cause of morbidity and the most frequent cause of death in cystathionine beta-synthase deficiency. Vascular occlusion can occur in any vessel and at any age, including infancy (39). By the end of the third decade, 50% of untreated patients have had one or more thromboembolic events (65). The international survey of Mudd and colleagues revealed that 158 (of 629) patients were reported to have had a total of 253 thromboembolic events. Among these events, 51% involved peripheral veins (of which about a quarter resulted in pulmonary embolism), 32% were cerebrovascular accidents, 11% affected peripheral arteries, 4% produced myocardial infarctions, and 2% fell into none of these categories (65).
Central nervous system. Intellectual disability of varying severity is the most common manifestation of central nervous system involvement in the disease. Presenting as developmental delay during the first years of life, intellectual disability is often the first recognized sign of cystathionine beta-synthase deficiency. The cognitive capability of untreated patients varies widely. IQ scores range from 10 to 138, with a median of approximately 64 (65). IQ scores among affected siblings were similar (01). Seizures occur in about 20% of untreated patients (65). The most common seizure type is generalized tonic-clonic. Typical strokes or focal neurologic signs suggest the presence of a cerebrovascular occlusion. Other neurologic features have included abnormal electroencephalograms and extrapyramidal disturbances, such as dystonia (01; 38). Diffuse leukoencephalopathy, observed in 3 cases to date, is an extremely rare finding in classical homocystinuria. In all the cases the leukoencephalopathy was reversible, and it was complicated by severe hypermethioninemia (greater than 1000 µmol/L). Thus, brain edema rather than demyelination was the most likely cause for leukoencephalopathy (88; 16; 82). Psychiatric abnormalities have been reported in about a half of one series of 63 patients. Four diagnostic categories predominated: episodic depression (10%), chronic disorders of behavior (17%), chronic obsessive-compulsive disorder (5%), and personality disorders (19%) (01). Another series investigating neuropsychiatric outcomes noted psychological symptoms in 16 of 25 adult patients (64%), including a high prevalence of anxiety (32%) and depression (32%) that correlated with IQ values below 85 (03).
Risk for development of Alzheimer diseases is likely greater based on the observation that increased plasma homocysteine represents an independent risk factor. With a plasma homocysteine level greater than 14 µmol per liter, the risk of Alzheimer disease nearly doubles (76).
All of the above-mentioned clinical manifestations except for the skeletal manifestation are commonly more pronounced or occur earlier in pyridoxine nonresponsive patients as compared to those who are pyridoxine responsive. The skeletal manifestations do not appear to depend on the pyridoxine responsiveness of patients. In a more granular analysis regarding pyridoxine responsiveness, 328 patients with CBS deficiency were classified into 4 groups of pyridoxine responsivity: nonresponders, partial, full, and extreme responders (41). Lens dislocation was common in all groups except extreme responders, but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the nonresponder group, whereas no extreme responder patient had cognitive impairment. Thromboembolism was the commonest presenting feature in extreme responder patients, whereas it was least likely at presentation in the nonresponder group. This probably is due to the differences in ages at presentation. All groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Along those lines, Ochoa-Ferraro and colleagues reported cerebral venous thrombosis as the first manifestation of homocystinuria in adults (67).
Biological basis
Etiology and pathogenesis
Homocystinuria is an autosomal recessive inherited disorder due to deficiency of cystathionine beta-synthase (EC 4.2.1.22, McKusick 236200). The gene has been cloned and mapped to chromosome 21 in the subtelomeric area q22.3 (66). The human cystathionine beta-synthase cDNA sequence and structure was published in 1993 (43). More than 320 individual homocystinuric alleles have been studied, and 100 mutations were detected. Most of these mutations are missense mutations (42). Testing for pathogenicity revealed that mutations p.M173del, p.I278S, p.D281N, and p.D321V showed null activity in all conditions tested, whereas mutations p.49L, p.P200L, and p.A446S retained different degrees of activity and response to stimulation (15). In a series of 84 cystathionine beta-synthase alleles previously sequenced from patients with homocystinuria, 37% of the alleles were partially functional or could be rescued by cofactor supplementation (55). Deficient regulation of cystathionine beta-synthase by its activator S-adenosylmethionine seems to be a frequently found mechanism in 20% of individuals with cystathionine beta-synthase deficiency (57).
Cystathionine beta-synthase activity can be found in many tissues, including liver, brain, pancreas, and cultured fibroblasts (79). The enzyme is a tetramer of identical 63-kDa subunits but can also exist as a more active dimer of 48-kDa subunits (44). In addition to the cofactor pyridoxal phosphate, cystathionine beta-synthase also binds to other ligands: the activator S-adenosylmethionine and 1 mole of heme per subunit (40; 23).
Fibroblasts from patients with homocystinuria due to cystathionine beta-synthase deficiency can be classified into 3 groups: those exhibiting no residual activity, those exhibiting reduced activity with normal affinity for pyridoxal phosphate, and those exhibiting residual activity with markedly reduced affinity for pyridoxal phosphate (22). The in vitro properties do not necessarily correspond to in vivo responsiveness to pyridoxine, but in almost all pyridoxine responders there is at least a small amount of residual enzymatic activity detectable in fibroblasts. Nevertheless, there is ample evidence that the pyridoxine-induced response in patients is due to its action as a cofactor of cystathionine beta-synthase. Approximately equal proportions of patients are pyridoxine responsive and nonresponsive (65; 14).
Not all of the pyridoxine-responsive patients reveal complete normalization of homocysteine after pyridoxine treatment. Some patients who are responsive to pyridoxine continue to have slight elevations of homocysteine in plasma and urine. Brenton and Cusworth defined 3 classes of pyridoxine responsiveness, including a group intermediate between those who display little or no response and those with clear response (11). Approximately 13% of patients may show such intermediate responses (65).
Kožich and colleagues have analyzed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry and developed comprehensive criteria to classify patients into 4 groups of pyridoxine responsivity: nonresponders, partial, full, and extreme responders (41). All groups showed overlapping concentrations of plasma total homocysteine, whereas pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The full and extreme responder groups had a later age of onset and diagnosis and a longer diagnostic delay than nonresponder and partial responder patients.
Deficiency of cystathionine beta-synthase leads to tissue accumulation of methionine, homocysteine, and their S-adenosyl derivatives, with lack of cystathionine and low levels of cysteine. Thus, cysteine becomes an essential amino acid in cystathionine beta-synthase deficiency. The –SH group of homocysteine can easily react with –SH groups of other molecules, leading to the formation of a number of disulfide compounds, such as homocystine, homocysteine-cysteine mixed disulfide, or protein-bound homocysteine (06).
The pathophysiology of cystathionine beta-synthase deficiency has not yet been completely elucidated, but accumulation of homocysteine probably plays a major role in determining some of the most relevant clinical manifestations, including generalized vascular damage and thromboembolic complications. This view is supported by the observation that patients with cystathionine beta-synthase deficiency due to defects of remethylation, but without accumulation of methionine, show similar lesions in blood vessels (08).
Thromboembolism has been suggested to be the end-point of homocysteine-induced abnormalities of platelets, endothelial cells, and coagulation factors. Homocysteine may also cause abnormal cross-linking of collagen (71), leading to abnormalities of the skin, joints, and skeleton in patients (51). Impaired cartilage differentiation has been demonstrated in cystathionine beta-synthase deficient mice (73). These mechanisms seem unlikely to cause damage of the non-collagenous zonular fibers of the lens; instead, disturbed fibrillin structure has been proposed (63; 86). Investigations on the potential of homocysteine to modify structural and functional properties of recombinant human fibrillin-1 fragments strongly suggest that structural and functional modifications as well as degradation processes of fibrillin-1 in the connective tissues of patients with homocystinuria play a major role in the pathogenesis of this disorder (34; 33).
It has not yet been elucidated how cystathionine beta-synthase deficiency impairs cognitive capabilities. Increased homocysteine is considered a risk factor for vascular dementia and stroke. Research results in murine models suggest that homocysteine causes arterial remodeling, at least in part, by increasing the collagen/elastin ratio. This increases vascular resistance that leads to a decrease in carotid artery blood flow (46). Other studies have attempted to clarify the mechanisms involved in the complex neuropathological features associated with abnormal homocysteine metabolism. Investigations on the effect of elevated homocysteine on the blood-brain barrier suggest an important toxic effect of elevated homocysteine on brain microvessels and implicate homocysteine in the disruption of the blood-brain barrier (36). Investigations on the regional and cellular distribution of cystathionine beta-synthase in the adult and developing mouse brain suggest that the enzyme plays a crucial role in the development and maintenance of the CNS and that enzyme deficiency might cause radial glia or astrocyte dysfunction (17).
Epidemiology
The estimated prevalence of cystathionine beta-synthase deficiency ranges from 1 in 1800 newborns in the state of Qatar and over 1 in 50,000 in Ireland and Kuwait to 1 in 1 million in Japan (91; 04). The overall frequency has been reported to be between 1 in 200,000 and 1 in 335,000 (64). Moorthie and colleagues performed a systematic review and metaanalysis and found a worldwide prevalence based on diagnosis of symptomatic individuals of 0.82 in 100,000, whereas the prevalence based on neonatal screening by MS/MS was 1.01 in 100,000 newborns (58). The minimum worldwide prevalence of homocystinuria based on the frequency of the 25 most common pathogenic alleles of homocystinuria in a large genomic database (gnomAD) was estimated to be about 0.38 in 100,000 and was higher in non-Finnish Europeans (approximately 0.72:100,000) and Latin Americans (approximately 0.45:100,000), and lower in Africans (approximately 0.20:100,000) and Asians (approximately 0.02:100,000) (85).
Data for the frequency of cystathionine beta-synthase deficiency are derived from the number of patients detected by newborn screening for cystathionine beta-synthase deficiency, though a measurement of methionine is likely an underestimate of the true rate of occurrence of cystathionine beta-synthase deficiency. Particularly, the pyridoxine-responsive cystathionine beta-synthase deficiency, the most readily treatable form, is being preferentially missed by newborn screening. This is corroborated by some studies on allele frequencies. A DNA-based screening of newborns in Denmark showed 1.4% of them to be heterozygous for the I278T mutation (28). This value corresponds to a homozygote frequency of approximately 1:20,000. In the Czech population, the frequency of the c.1105C>T mutation, which typically causes a milder phenotype, was 0.005. This predicts a birth prevalence of homocystinuria of 1:40,000, which increased to 1:15,500 in a model that included 10 additional mutations (35). Skovby and colleagues concluded that the predominant portion of such homozygotes are clinically unaffected or may be identified due to thromboembolic events that occur no sooner than the third decade of life (78).
Prevention
From observation in patients in whom homocystinuria was detected early and treated, some evidence indicates that presymptomatic initiation of treatment is able to prevent cognitive impairment, lens dislocation, and thromboembolic events (65). This is especially important in pyridoxine-responsive forms. Newborn screening for cystathionine beta-synthase deficiency would represent the tool for the required timely identification of affected patients. Although it is not possible to draw any conclusions based on controlled studies, there are uncontrolled case series that support the efficacy of newborn screening for homocystinuria and its early treatment (83). Newborn screening programs searching for the disease by methionine measurement may fail because of their insufficient diagnostic sensitivity of methionine, which is not dependent on the screening technology (75). To overcome the lack of sensitivity of methionine screening, total homocysteine has been implemented successfully as a first tear test in Qatar (29); however, low prevalence of the disease in most parts of the world may not justify the incremental cost that would come with homocysteine as a first tear test. Instead, lowering the methionine cut-off combined with additional ratios, like the methionine/phenylalanine ratio, or the combination with total homocysteine as a secondary tear test may present cheaper alternatives to improve specificity and sensitivity of newborn screening for homocystinuria (37).
The implementation of a feasible method to measure total homocysteine in the newborn screening sample should overcome the problem (25). Indeed, various laboratories have reported the successful analysis of total homocysteine with liquid chromatography–mass spectrometry methods (24). A review of newborn screening practice for homocystinuria recommends the revision of decision limits considering population median, the combination of relevant screening markers, and tHcy as second-tier marker (37).
The risk for thromboembolic events seems to be directly correlated with the plasma homocysteine concentration. Normalization of plasma homocysteine at any time seems to prevent the occurrence of new thromboembolic events, but even when normalization cannot be reached by treatment, lowering the homocysteine concentration lowers the risk for such an event. Thus, lowering homocysteine as much as possible represents the most important measure in homocystinuric patients. Otherwise, the protection for vascular occlusions must be carried out by anticoagulants.
Differential diagnosis
The differential diagnosis for homocystinuria due to cystathionine beta-synthase deficiency is as follows:
Other hypermethioninemias (with mild hyperhomocysteinemia): | |
• S-adenosylhomocysteine hydrolase deficiency | |
Other hypermethioninemias (without hyperhomocysteinemia): | |
• Glycine N-methyltransferase deficiency | |
Other hyperhomocysteinemias (without hypermethioninemia): | |
• 5-MTHFR deficiency | |
Other syndromes sharing some clinical features with those of cystathionine beta-synthase deficiency: | |
• Marfan syndrome | |
Diagnostic workup
Determination of plasma total homocysteine and of plasma amino acids allows diagnosis of cystathionine beta-synthase deficiency. Total homocysteine in cystathionine beta-synthase deficiency is often higher than 200 µmol/L (reference, less than 15 µmol/L). Methionine is clearly increased in most cases (approximately 500 to 800 µmol/L, reference less than 35 µmol/L). Urinary analysis reveals increased homocystine and homocysteine-cysteine excretion. The cyanide nitroprusside test is positive. Confirmation analysis consists of cystathionine beta-synthase measurement in fibroblasts or plasma (02) and mutational analysis in the cystathionine beta-synthase gene. In vitro pyridoxine responsiveness of residual cystathionine beta-synthase enzyme activity in fibroblasts can be estimated by enzyme assay with and without addition of pyridoxine. However, the in vitro response does not reflect the in vivo response to pyridoxine in all patients. Before initiation of treatment, the in vivo response to pyridoxine has to be examined by administration of vitamin B6 (100 mg twice a day, over 2 weeks). After measuring total homocysteine, folate must be added (5 mg, over next 2 weeks). After 4 weeks, the patients can be considered to be pyridoxine-responsive when total homocysteine is less than 60 µmol/L, as pyridoxine-partially responsive when total homocysteine decreases but is greater than 60 µmol/L, and as pyridoxine-non-responsive when total homocysteine remains unchanged.
Prenatal diagnosis of cystathionine beta-synthase deficiency is feasible in chorionic villi and cultured amniotic cells.
A review from Morris and colleagues provides guidance for the diagnosis and management of homocystinuria (59).
Management
The goal of treatment in cystathionine beta-synthase deficiency is normalization of plasma total homocysteine. The target concentration is less than 20 µmol/L. Whenever normalization is not accessible, the total homocysteine concentration must be kept in the lowest range possible.
In addition, the total cysteine content in plasma is crucial. Plasma cysteine concentrations below 150 µmol/L counteract the efforts to lower plasma homocysteine. An exogenous supply of 40 mg cysteine/kg per day might be sufficient to maintain the glutathione synthesis in erythrocytes (48; 68; 80)
Several strategies used to lower homocysteine levels include:
(1) Enhancing transsulphuration by using pharmacological doses of vitamin B6
(2) Increasing remethylation by folate, vitamin B12, and betaine
(3) Reducing methionine load by a low protein diet combined with a methionine-free amino acid mixture, containing supplemented cysteine.
About half of all cystathionine beta-synthase deficiency patients are responsive to pharmacological doses of vitamin B6, and this treatment alone will substantially reduce plasma homocysteine levels. With treatment, all of these patients will eventually become folate depleted, and probably also B12 depleted, and these vitamins are essential. Occasionally, patients are partially responsive to pyridoxine. Most pyridoxine-responsive patients cannot achieve a normal level of homocysteine on pyridoxine, folate, and B12 treatment alone, although the levels obtained evidently result in a greatly improved outcome. Addition of a low protein diet and methionine-free amino acid supplement, if tolerated, will result in near-normal total homocysteine levels in most patients. Pyridoxine-nonresponsive patients need betaine in addition to folate, vitamins B12 and B6, and a low-protein diet with a methionine-free amino acid supplement. Usually, only patients diagnosed as neonates are fully compliant with diet and the amino acid supplement.
ad (1): | Younger than 2 years of age: Pyridoxine 50 mg daily |
Older than 2 years of age: Pyridoxine 50 to 100 mg twice daily. |
Some patients respond on higher doses of vitamin B6; however, doses greater than 400 mg daily have been associated with peripheral neuropathy in some individuals (09). Pyridoxine toxicity (respiratory failure and rhabdomyolysis) has been observed in one neonate receiving 200 mg pyridoxine (54 mg/kg/day) (05).
ad (2): | Younger than 2 years of age: folic acid 1 to 2 mg daily |
2 to 15 years of age: folic acid 5 mg daily, hydroxo- (cyano-) cobalamin orally 1 mg daily (alternatively intramuscular injection 1 mg monthly), betaine 1.5 to 3 g daily | |
Over 15 years of age: folic acid and hydroxo- (cyano-) cobalamin, hydroxycobalamin as above, betaine 3 g twice daily. |
Cerebral edema has been observed in a child with cystathionine beta-synthase deficiency 4 to 6 weeks after starting betaine therapy (16). The cerebral edema might have been provoked by a betaine-caused rapid increase of methionine. High plasma levels (greater than 1500 µmol/L) may possibly be associated with cerebral edema, although this is uncertain (60).
ad (3): | Younger than 2 years of age: restriction of natural protein (0.7 to 1.0 g/kg body weight per day), methionine-free essential amino acid mixture (1.8 to 1.5 g/kg body weight per day with meals) |
2 to 15 years of age: restriction of natural protein (0.7 to 1.0 g/kg body weight per day), methionine-free essential amino acid mixture (1.3 to 0.8 g/kg body weight per day with meals) | |
Over 15 years of age: restriction of natural protein (0.7 g/kg body weight per day), methionine-free essential amino acid mixture (0.7 to 0.3 g/kg body weight per day with meals). |
Aspirin (100 mg daily) is indicated if there are other thrombophilic factors present, such as factor V Leyden, or if there has been a thromboembolic event. Vitamin C has been shown to improve the impairment of nitric-oxide-dependent vasodilatation that occurs in cystathionine beta-synthase deficiency patients (72). Supplementation with the amino acid taurine improved preexisting reduced endothelial function in CBS-deficient patients (81).
The first case of liver transplantation intended to cure homocystinuria has been published, and the results are promising (50). A 24-year-old man with homocystinuria diagnosed and treated from birth received a deceased whole liver transplant. Because of poor adherence to the conventional diet-restrictive therapy, liver transplantation was considered when he developed hypertension and multiple infarctions over the right cerebellum early in the second decade of his life. Plasma and urine homocysteine and plasma methionine normalized, and he was completely disease free without dietary or nutritional control.
Chemical chaperone therapy might be a promising new approach in the future. Some studies have shown that proline, glycerol, sorbitol, ethanol, dimethyl sulfoxide, or trimethylamine-N-oxide can restore significant cystathionine beta-synthase enzymatic activity. The ratio of Hsp70 and Hsp26 determines whether misfolded human cystathionine beta-synthase will either be refolded or degraded. Heme arginate, for example, rescued catalytic CBS activity of 5 out of 7 human mutations in mammalian CHO-K1 cells (77; 53; 52; 56). Along those lines, proteostasis modulators may be useful in treating certain types of genetic diseases caused by missense mutations as they can restore significant enzymatic activity to misfolded cystathionine beta-synthase enzymes in mutant mice (30).
Attempts toward gene therapy indicate the efficacy and feasibility of gene delivery and long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy (70; 47).
Also, in mice, enzyme replacement therapy with PEGylated cystathionine beta synthase resulted in reduced and sustained plasma homocysteine concentration and normalized plasma cysteine, corrected liver glucose, and lipid metabolism and prevented or reversed facial alopecia, fragile and lean phenotype, and low bone mass (54).
Outcomes
Extreme variability of prognosis is a consequence of whether or not there are thromboembolic events and, if there are, which areas of the body suffer infarction. Variability also depends on whether the patients are pyridoxine-responsive or not and when the treatment was started. The outcome in 158 patients treated for up to 18 years has been reported (89). Those patients responsive to pyridoxine maintained total homocysteine levels of less than 60 µmol/L (reference less than 15 µmol/L), whereas pyridoxine-non-responsive patients had levels usually greater than 80 µmol/L. Treatment regimens varied somewhat. There was a substantial decrease in thromboembolic episodes from the number expected in untreated patients. In a subset of patients whose treatment was standardized and similar to that described below, the same benefit from this treatment regimen was seen (87). In patients with neonatal diagnosis and treatment, there is also evidence of improved outcome with avoidance of intellectual deficit and dislocation of the lens (90).
There is an increased risk for thromboembolic events from any surgery or immobilization and for acute glaucoma due to pupillary block by the dislocated lens.
Special considerations
Pregnancy
Pregnancy in cystathionine beta-synthase deficiency may well confer increased risk for maternal thromboembolism, especially postpartum, but there seems to be only limited teratogenic potential. Thromboembolic events have been reported previously in a few pregnancies, all occurring postpartum. Recommendation for anticoagulation during delivery is still controversial. Maternal cystathionine beta-synthase deficiency might predispose pregnant women to preeclampsia. Although only small numbers of pregnancies in cystathionine beta-synthase deficiency have been reported, most pregnancies have progressed without obstetric complications (49), and healthy pregnancies are feasible. That can be achieved by proactive management through a motivated clinical team and good patient engagement (31).
Anesthesia
Nitrous oxide might have adverse effects on increasing homocysteine levels because it irreversibly deactivates methionine synthase; therefore, it should not be used as an anesthetic agent.
Media
References
- 01
- Abbott MH, Folstein SE, Abbey H, Pyeritz RE. Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet 1987;26(4):959-69. PMID 3591841
- 02
- Alcaide P, Krijt J, Ruiz-Sala P, et al. Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS. Clin Chim Acta 2015;438:261-5. PMID 25218699
- 03
- Almuqbil MA, Waisbren SE, Levy HL, Picker JD. Revising the psychiatric phenotype of homocystinuria. Genet Med 2019;21(8):1827-31. PMID 30643218
- 04
- Alsharhan H, Ahmed AA, Ali NM, et al. Early diagnosis of classic homocystinuria in kuwait through newborn screening: A 6-year experience. Int J Neonatal Screen 2021;7(3):56. PMID 34449519
- 05
- Ames EG, Scott AJ, Pappas KB, Moloney SM, Conway RL, Ahmad A. A cautionary tale of pyridoxine toxicity in cystathionine beta-synthase deficiency detected by two-tier newborn screening highlights the need for clear pyridoxine dosing guidelines. Am J Med Genet A 2020;182(11):2704-8. PMID 32820583
- 06
- Andria G, Fowler B, Sebastio G. Disorders of sulfur amino acid metabolism. In: Fernandes J, Saudubray JM, van den Berghe G, editors. Inborn Metabolic Diseases. Diagnosis and Treatment. Berlin, Heidelberg, New York, Barcelona, Hong Kong, London, Milano, Paris, Singapore: Springer, 2000:225-31.
- 07
- Barber GW, Spaeth GL. Pyridoxine therapy in homocystinuria. Lancet 1967;1:337.
- 08
- Baumgartner R, Wick H, Ohnacker H, Probst A, Maurer R. Vascular lesions in two patients with congenital homocystinuria due to different defects of remethylation. J Inherit Metab Dis 1980;3(3):101-3. PMID 6775136
- 09
- Bendich A, Cohen M. Vitamin B6 safety issues. Ann N Y Acad Sci 1990;585:321-30. PMID 2192616
- 10
- Brenton DP. Skeletal abnormalities in homocystinuria. Postgrad Med J 1977;53(622):488-96. PMID 917963
- 11
- Brenton DP, Cusworth DC. The response of patients with cystathionine synthase deficiency to pyridoxine. In: Carson NA, Raine DN, editors. Inherited Disorders of Sulphur Metabolism. London: Churchill, Livingstone, 1971:264.
- 12
- Carson NA, Cusworth DC, Dent CE, Field CMB, Neill DW, Westall RG. Homocystinuria: a new inborn error of metabolism associated with mental deficiency. Arch Dis Child 1963;38:425-36. PMID 14065982
- 13
- Carson NA, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child 1962;37:505-13. PMID 14018926
- 14
- Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 2006;29(2-3):317-26. PMID 16763894
- 15
- Cozar M, Urreizti R, Vilarinho L, et al. Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients. Hum Mutat 2011;32(7):835-42. PMID 21520339
- 16
- Devlin AM, Hajipour L, Gholkar A, Fernandes H, Ramesh V, Morris AA. Cerebral edema associated with betaine treatment in classical homocystinuria. J Pediatr 2004;144(4):545-8. PMID 15069409
- 17
- Enokido Y, Suzuki E, Iwasawa K, Namekata K, Okazawa H, Kimura H. Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS. FASEB J 2005;19(13):1854-6. PMID 16160063
- 18
- Ereno-Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez-Cruz LA. Purification, crystallization and preliminary crystallographic analysis of the catalytic core of cystathionine beta-synthase from Saccharomyces cerevisiae. Acta Crystallogr F Struct Biol Commun 2014;70(Pt 3):320-5. PMID 24598918
- 19
- Ereno-Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez-Cruz LA. Structural basis of regulation and oligomerization of human cystathionine β-synthase, the central enzyme of transsulfuration. Proc Natl Acad Sci U S A 2013;110(40):E3790-9. PMID 24043838
- 20
- Field CM, Carson NA, Cusworth DC, Dent CE, Neill DW. Homocystinuria: a new disorder of metabolism [abstract.]. In: Abstracts of the Tenth International Congress of Pediatrics (Lisbon), 1962:274.
- 21
- Finkelstein JD, Mudd SH, Irreverre F, Laster L. Homocystinuria due to cystathionine synthase deficiency: the mode of inheritance. Science 1964;146:785-7. PMID 14197572
- 22
- Fowler B, Kraus J, Packman S, Rosenberg LE. Homocystinuria: evidence for three distinct classes of cystathionine beta-synthase mutants in cultured fibroblasts. J Clin Invest 1978;61(3):645-53. PMID 641146
- 23
- Frank N, Kent JO, Meier M, Kraus JP. Purification and characterization of the wild type and truncated human cystathionine beta-synthase enzymes expressed in E. coli. Arch Biochem Biophys 2008;470(1):64-72. PMID 18060852
- 24
- Fu X, Xu YK, Chan P, Pattengale PK. Simple, fast, and simultaneous detection of plasma total homocysteine, methylmalonic acid, methionine, and 2-methylcitric acid using liquid chromatography and mass spectrometry (LC/MS/MS). JIMD Rep 2013;10:69-78. PMID 23430805
- 25
- Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, et al. Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 2010;156(3):427-32. PMID 19914636
- 26
- Gaull G, Sturman JA, Schaffner F. Homocystinuria due to cystathionine synthase deficiency: enzymatic and ultrastructural studies. J Pediatr 1974;84(3):381-90. PMID 4811988
- 27
- Gaull GE, Rassin DK, Sturman JA. Enzymatic and metabolic studies of homocystinuria: effects of pyridoxine. Neuropädiatrie 1969;1(2):199-226.
- 28
- Gaustadnes M, Ingerslev J, Rutiger N. Prevalence of congenital homocystinuria in Denmark. N Engl J Med 1999;340(19):1513. PMID 10328723
- 29
- Gramer G, Abdoh G, Ben-Omran T, et al. Newborn screening for remethylation disorders and vitamin B12 deficiency-evaluation of new strategies in cohorts from Qatar and Germany. World J Pediatr 2017;13(2):136-43. PMID 28101774
- 30
- Gupta S, Wang L, Anderl J, Slifker MJ, Kirk C, Kruger WD. Correction of cystathionine β-synthase deficiency in mice by treatment with proteasome inhibitors. Hum Mutat 2013;34(8):1085-93. PMID 23592311
- 31
- Hart C, McNulty J, Cotter M, Al Jasmi F, Crushell E, Monavari AA. The challenges of pregnancy management in pyridoxine nonresponsive homocystinuria: The Irish experience. JIMD Rep 2021;61(1):34-41. PMID 34485015
- 32
- Hu FL, Gu Z, Kozich V, Kraus JP, Ramesh V, Shih VE. Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria. Hum Mol Genet 1993;2(11):1857-60. PMID 7506602
- 33
- Hubmacher D, Sabatier L, Annis DS, Mosher DF, Reinhardt DP. Homocysteine modifies structural and functional properties of fibronectin and interferes with the fibronectin-fibrillin-1 interaction. Biochemistry 2011;50(23):5322-32. PMID 21561146
- 34
- Hubmacher D, Tiedemann K, Bartels R, et al. Modification of the structure and function of fibrillin-1 by homocysteine suggests a potential pathogenetic mechanism in homocystinuria. J Biol Chem 2005;280(41):34946-55. PMID 16096271
- 35
- Janosik M, Sokolova J, Janosikova B, Krijt J, Klatovska V, Kozich V. Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta-synthase gene. J Pediatr 2009;154(3):431-7. PMID 18950795
- 36
- Kamath AF, Chauhan AK, Kisucka J, et al. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 2006;107(2):591-3. PMID 16189268
- 37
- Keller R, Chrastina P, Pavlikova M, et al. Newborn screening for homocystinurias: recent recommendations versus current practice. J Inherit Metab Dis 2019;42(1):128-39. PMID 29943221
- 38
- Kempster PA, Brenton DP, Gale AN, Stern GM. Dystonia in homocystinuria. J Neurol Neurosurg Psychiatry 1988;51(6):859-62. PMID 3404194
- 39
- Kerrin D, Murdoch ED, Livingston J, Henderson M, Smith M. Homocystinuria presenting with sagittal sinus thrombosis in infancy. J Child Neurol 1996;11(1):70-1. PMID 8745393
- 40
- Kery V, Bukovska G, Kraus JP. Transsulfuration depends on heme in addition to pyridoxal 5'-phosphate. Cystathionine beta-synthase is a heme protein. J Biol Chem 1994;269(41):25283-8. PMID 7929220
- 41
- Kozich V, Sokolova J, Morris AAM, Pavlikova M, Gleich F, Kolker S, et al. Cystathionine beta-synthase deficiency in the E-HOD registry-part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis. J Inherit Metab Dis 2021;44(3):677-92. PMID 33295057
- 42
- Kraus J, Janosik M, Kozich V, et al. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat 1999;13(5):362-75. PMID 10408774
- 43
- Kraus J, Le K, Swaroop M, et al. Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells. Hum Mol Genet 1993;2(10):1633-8. PMID 7903580
- 44
- Kraus J, Packman S, Fowler B, Rosenberg LE. Purification and properties of cystathionine beta-synthase from human liver. Evidence for identical subunits. J Biol Chem 1978;253(18):6523-8. PMID 681363
- 45
- Kruger WD. How to fix a broken protein: restoring function to mutant human cystathionine beta-synthase. Hum Genet 2022;141(7):1299-308. PMID 34636997
- 46
- Kumar M, Tyagi N, Moshal KS, et al. Homocysteine decreases blood flow to the brain due to vascular resistance in carotid artery. Neurochem Int 2008;53(6-8):214-9. PMID 18725259
- 47
- Lee HO, Salami CO, Sondhi D, Kaminsky SM, Crystal RG, Kruger WD. Long-term functional correction of cystathionine beta-synthase deficiency in mice by adeno-associated viral gene therapy. J Inherit Metab Dis 2021;44(6):1382-92. PMID 34528713
- 48
- Lee PJ, Briddon A. A rationale for cystine supplementation in severe homocystinuria. J Inherit Metab Dis 2007;30(1):35-8. PMID 17186416
- 49
- Levy HL, Vargas JE, Waisbren SE, et al. Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency. J Inherit Metab Dis 2002;25(4):299-314. PMID 12227460
- 50
- Lin NC, Niu DM, Loong CC, et al. Liver transplantation for a patient with homocystinuria. Pediatr Transplant 2012;16(7):E311-4. PMID 22360426
- 51
- Lubec B, Fang-Kircher S, Lubec T, Blom HJ, Boers GH. Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta 1996;1315(3):159-62. PMID 8611653
- 52
- Majtan T, Jones W Jr, Krijt J, et al. Enzyme replacement therapy ameliorates multiple symptoms of murine homocystinuria. Mol Ther 2018a;26(3):834-44. PMID 29398487
- 53
- Majtan T, Liu L, Carpenter JF, Kraus JP. Rescue of cystathionine beta-synthase (CBS) mutants with chemical chaperones: purification and characterization of eight CBS mutant enzymes. J Biol Chem 2010;285(21):15866-73. PMID 20308073
- 54
- Majtan T, Pey AL, Gimenez-Mascarell P, et al. Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria. Handb Exp Pharmacol 2018b;245:345-83. PMID 29119254
- 55
- Mayfield JA, Davies MW, Dimster-Denk D, et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics 2012;190(4):1309-23. PMID 22267502
- 56
- Melenovska P, Kopecká J, Krijt J, et al. Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. J Inherit Metab Dis 2015;38(2):287-94. PMID 25331909
- 57
- Mendes MI, Colaco HG, Smith DE, et al. Reduced response of cystathionine beta-synthase (CBS) to S-adenosylmethionine (SAM): Identification and functional analysis of CBS gene mutations in Homocystinuria patients. J Inherit Metab Dis 2014;37(2):245-54. PMID 23974653
- 58
- Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis 2014;37(6):889-98. PMID 25022222
- 59
- Morris AA, Kozich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis 2017;40(1):49-74. PMID 277778219
- 60
- Mudd SH, Cerone R, Schiaffino MC, et al. Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia. J Inherit Metab Dis 2001;24(4):448-64. PMID 11596649
- 61
- Mudd SH, Edwards WA, Loeb PM, Brown MS, Laster L. Homocystinuria due to cystathionine synthase deficiency: the effect of pyridoxine. J Clin Invest 1970;49(9):1762-73. PMID 5449710
- 62
- Mudd SH, Finkelstein JD, Irreverre F, Laster L. Homocystinuria: an enzymatic defect. Science 1964;143:1443-5. PMID 14107447
- 63
- Mudd SH, Levy HL, Kraus JP. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2000:2007-56.
- 64
- Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 1989:693.
- 65
- Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta- synthase deficiency. Am J Hum Genet 1985;37(1):1-31. PMID 3872065
- 66
- Munke M, Kraus JP, Ohura T, Francke U. The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17. Am J Hum Genet 1988;42(4):550-9. PMID 2894761
- 67
- Ochoa-Ferraro A, Wanninayake S, Dawson C, Gerrard A, Preece MA, Geberhiwot T. A case series of cerebral venous thrombosis as the first manifestation of homocystinuria. Eur Stroke J 2021;6(4):420-7. PMID 35342812
- 68
- Okawa H, Morita T, Sugiyama K. Cysteine supplementation decreases plasma homocysteine concentration in rats fed on a low-casein diet in rats. Biosci Biotechnol Biochem 2007;71(1):91-7. PMID 17213675
- 69
- Oyenarte I, Majtan T, Ereno J, Corral-Rodriguez MA, Kraus JP, Martinez-Cruz LA. Purification, crystallization and preliminary crystallographic analysis of human cystathionine β-synthase. Acta Crystallogr Sect F Struct Biol Cryst Commun 2012;68(Pt 11):1318-22. PMID 23143241
- 70
- Park ES, Oh HJ, Kruger WD, Jung SC, Lee JS. Recombinant adeno-associated virus mediated gene transfer in a mouse model for homocystinuria. Exp Mol Med 2006;38(6):652-61. PMID 17202841
- 71
- Perla-Kajan J, Utyro O, Rusek M, Malinowska A, Sitkiewicz E, Jakubowski H. N-Homocysteinylation impairs collagen cross-linking in cystathionine beta-synthase-deficient mice: a novel mechanism of connective tissue abnormalities. FASEB J 2016;30(11):3810-21. PMID 27530978
- 72
- Pullin CH, Bonham JR, McDowell IF, et al. Vitamin C therapy ameliorates vascular endothelial dysfunction in treated patients with homocystinuria. J Inherit Metab Dis 2002;25(2):107-18. PMID 12118525
- 73
- Robert K, Maurin N, Vayssettes C, Siauve N, Janel N. Cystathionine beta synthase deficiency affects mouse endochondral ossification. Anat Rec A Discov Mol Cell Evol Biol 2005;282(1):1-7. PMID 15622513
- 74
- Schedewie H, Willich E, Grobe H, Schmidt H, Muller KM. Skeletal findings in homocystinuria: a collaborative study. Pediatr Radiol 1973;1(1):12-23. PMID 4768238
- 75
- Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 2003;111(6 Pt 1):1399-406. PMID 12777559
- 76
- Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346(7):476-83. PMID 11844848
- 77
- Singh LR, Chen X, Kozich V, Kruger WD. Chemical chaperone rescue of mutant human cystathionine beta-synthase. Mol Genet Metab 2007;91(4):335-42. PMID 17540596
- 78
- Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab 2010;99(1):1-3. PMID 19819175
- 79
- Uhlendorf BW, Mudd SH. Cystathionine synthase in tissue culture derived from human skin: enzyme defect in homocystinuria. Science 1968;160(831):1007-9. PMID 5647845
- 80
- van der Crabben SN, Wijburg FA, Ackermans MT, Sauerwein HP. Effect of cysteine dosage on erythrocyte glutathione synthesis rate in a patient with cystathionine beta synthase deficiency. J Inherit Metab Dis 2008. PMID 18213523
- 81
- Van Hove JLK, Freehauf CL, Ficicioglu C, et al. Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine B-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial. J Inherit Metab Dis 2019;42(3):424-37. PMID 30873612
- 82
- Vatanavicharn N, Pressman BD, Wilcox WR. Reversible leukoencephalopathy with acute neurological deterioration and permanent residua in classical homocystinuria: A case report. J Inherit Metab Dis 2008. PMID 18210212
- 83
- Walter JH, Jahnke N, Remmington T. Newborn screening for homocystinuria. Cochrane Database Syst Rev 2013;8:CD008840. PMID 23908001
- 84
- Weber DR, Coughlin C, Brodsky JL, et al. Low bone mineral density is a common finding in patients with homocystinuria. Mol Genet Metab 2016;117(3):351-4. PMID 26689745
- 85
- Weber Hoss GR, Sperb-Ludwig F, Schwartz IVD, Blom HJ. Classical homocystinuria: A common inborn error of metabolism? An epidemiological study based on genetic databases. Mol Genet Genomic Med 2020;8(6):e1214. PMID 32232870
- 86
- Whiteman P, Hutchinson S, Handford PA. Fibrillin-1 misfolding and disease. Antioxid Redox Signal 2006;8(3-4):338-46. PMID 16677079
- 87
- Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria--the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309(8):448-53. PMID 6877313
- 88
- Yaghmai R, Kashani AH, Geraghty MT, et al. Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency. Am J Med Genet 2002;108(1):57-63. PMID 11857551
- 89
- Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol 2001a;21(12):2080-5. PMID 11742888
- 90
- Yap S, Rushe H, Howard PM, Naughten ER. The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency. J Inherit Metab Dis 2001b;24(4):437-47. PMID 11596648
- 91
- Zschocke J, Kebbewar M, Gan-Schreier H, et al. Molecular neonatal screening for homocystinuria in the Qatari population. Hum Mutat 2009;30(6):1021-2. PMID 19370759
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Andreas Schulze MD PhD
Dr. Schulze of the University of Toronto and Section Head, Metabolic Genetics, and Medical Director, Newborn Screening Program, The Hospital for Sick Children, has no relevant financial relationships to disclose.
See Profile
Editor
-
Deepa S Rajan MD
Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
See Profile
Former Authors
- Lisa Emrick MD
Patient Profile
- Age range of presentation
-
- 0 month to 44 years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity typical
- autosomal recessive
- Over 85% of the described mutations in CBS-deficient patients are missense mutations in which the mutant protein fails to fold into an active conformation (Kruger 2022).
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-9
-
- Homocystinuria: 270.4
- ICD-10
-
- Homocystinuria: E72.1
- OMIM
-
- Homocystinuria: +236200
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
Neurogenetic Disorders
Pyruvate carboxylase deficiency
Nov. 09, 2024
-
Neurogenetic Disorders
Pelizaeus-Merzbacher disease
Oct. 31, 2024
-
Neurogenetic Disorders
Vanishing white matter disease
Oct. 30, 2024
-
Neurogenetic Disorders
Wilson disease
Oct. 23, 2024
-
Neurogenetic Disorders
Aromatic L-amino acid decarboxylase deficiency
Sep. 13, 2024
-
Stroke & Vascular Disorders
White matter abnormalities in the brain
Sep. 12, 2024
-
Neurogenetic Disorders
Hypermethioninemia
Sep. 12, 2024